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How to reap the benefits of exercise: It's in the genes

Baylor College of Medicine

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IMAGE: TFEB acts as a central coordinator of skeletal muscle insulin sensitivity, glucose homeostasis, lipid oxidation, and mitochondrial function in the adaptive metabolic response to physical exercise in a PGC1a-independent manner.... view more

Credit: Mansueto et al., 2017, Cell Metabolism 25, 1-15

An international team of scientists at Baylor College of Medicine, the Telethon Institute of Genetics and Medicine in Naples, Italy and other institutions has discovered that the gene TFEB is a major regulator of muscle function during exercise. Exercise triggers TFEB entering into the nucleus of muscle cells where it regulates the processes that provide energy to the muscle. These genes include those involved in glucose use, insulin sensitivity and function of the mitochondria, the energy-producer structures inside cells. This work may lead to the design of future treatments for conditions such as diabetes, obesity and metabolic syndrome. The study appears in Cell Metabolism.

In a previous study, the researchers found that TFEB can regulate the response of cells to food deprivation.

"In this study we found that TFEB controls the response of the body to physical exercise," said co-senior author Dr. Andrea Ballabio, professor of molecular and human genetics at Baylor and director of the Telethon Institute of Genetics and Medicine. "TFEB plays a central role by regulating the expression of genes that allow muscle cells to use energy." TFEB is a transcription factor - a master regulator molecule inside the cell that controls the expression and function of genes.

Uncovering the role of TFEB in exercise

The scientists studied the role of TFEB in the laboratory mouse. When the researchers knocked out the mouse TFEB gene, the mice had a hard time sustaining exercise. A closer look inside the cells showed that the mitochondria looked abnormal and were dysfunctional. The cells in the exercising muscle could not generate enough energy to sustain physical activity. In contrast, when the scientists overexpressed the TFEB gene in mice, the mitochondria looked healthy and increased the amount of energy they normally produced.

The researchers were surprised by these results. "TFEB had not been associated with how cells use energy before," Ballabio said.

"This work is the product of a very fruitful international collaboration among researchers in laboratories in Italy, the UK, China and the U.S.," said Ballabio. "Our discovery of a central pathway that regulates muscle metabolism, use of glucose and mitochondrial function may have important implications in the study of diseases such as obesity and diabetes, as well as in a number of diseases in which muscle function is compromised."

Future studies aimed at identifying drugs that modulate this pathway may lead to the identification of new strategies to treat such diseases.

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Other contributors of this work include Gelsomina Mansueto, Andrea Armani, Carlo Viscomi, Luca D'Orsi, Rossella De Cegli, Elena V. Polishchuk, Costanza Lamperti, Ivano Di Meo, Vanina Romanello, Silvia Marchet, Pradip K. Saha, Haihong Zong, Bert Blaauw, Francesca Solagna, Caterina Tezze, Paolo Grumati, Paolo Bonaldo, Jeffrey E. Pessin, Massimo Zeviani and Marco Sandri.

The researchers are affiliated with one or more of the following institutions: Telethon Institute of Genetics and Medicine; University of Padova; MRC Mitochondrial Biology Unit, Cambridge; Istituto Neurologico; Venetian Institute of Molecular Medicine; North Sichuan Medical College; Albert Einstein College of Medicine; Federico II University, Texas Children's Hospital and Baylor College of Medicine.

Financial support was provided by the Italian Telethon Foundation (TCR09003, TCP04009), the European Research Council (ERC 250154-CLEAR and 282310-MyoPHAGY), the Italian Ministry of Education (MiUR) (PRIN 2010/2011), CARIPARO and Foundation Leducq. In addition, support came from the University of Pennsylvania and Beyond Batten Disease Foundation, the Core Grant (MRC-MBU and ERC FP7-322424, GR-2010-2306-756), the Italian Ministry of Health and the National Science Foundation of China (H0315: 81370531).

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